{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T19:15:24Z","timestamp":1775848524553,"version":"3.50.1"},"reference-count":76,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T00:00:00Z","timestamp":1703635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"VA Merit Award","award":["I01CX001923-01"],"award-info":[{"award-number":["I01CX001923-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-\u03baB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-\u03b2 (TGF-\u03b2) production. Mechanistically, TGF-\u03b2- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21\/PTEN\/AKT signaling.<\/jats:p>","DOI":"10.3390\/cells13010056","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T05:43:15Z","timestamp":1703655795000},"page":"56","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance"],"prefix":"10.3390","volume":"13","author":[{"given":"Ayushi","family":"Trivedi","sequence":"first","affiliation":[{"name":"Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dipro","family":"Bose","sequence":"additional","affiliation":[{"name":"Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6173-9798","authenticated-orcid":false,"given":"Punnag","family":"Saha","sequence":"additional","affiliation":[{"name":"Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subhajit","family":"Roy","sequence":"additional","affiliation":[{"name":"Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhura","family":"More","sequence":"additional","affiliation":[{"name":"Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Skupsky","sequence":"additional","affiliation":[{"name":"Long Beach VA Medical Center, Long Beach, CA 90822, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy G.","family":"Klimas","sequence":"additional","affiliation":[{"name":"Institute for Neuro-Immune Medicine, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1649-7149","authenticated-orcid":false,"given":"Saurabh","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA"},{"name":"Long Beach VA Medical Center, Long Beach, CA 90822, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1136\/bmj.318.7179.274","article-title":"Gulf war syndrome","volume":"318","author":"Murphy","year":"1999","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1097\/00005053-200005000-00002","article-title":"Deployment stressors and a chronic multisymptom illness among Gulf War veterans","volume":"188","author":"Nisenbaum","year":"2000","journal-title":"J. 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